Derivatives of dicarboxylic acid having pharmaceutical properties

ABSTRACT

The invention relates to compounds of the general formula (I) 
                 
 
wherein R 1  represents H, halogen, or OCF 3 ; R 2  and R 3  each represents H or halogen; R 4  represents C 1-6 -alkyl, C 3-8 -cycloalkyl, CF 3 , OCF 3 , F, Cl, OMe, or optionally substituted phenyl; V represents O, CH 2 O, OCF 2 , or O—C 1-6 -alkyl-O; and W represents CH 2  or CH 2 CH 2 . A process for making such compounds, pharmaceutical compositions containing them, and methods of treatment of various conditions using them are also disclosed and claimed.

The present invention relates to novel aminocarboxylic acid derivativeswhich stimulate soluble guanylate cyclase also via a novel mechanism ofaction which takes place without involvement of the heme group of theenzyme, to their preparation and to their use as medicaments, inparticular as medicaments for treating cardiovascular disorders.

One of the most important cellular transmission systems in mammaliancells is cyclic guanosine monophosphate (cGMP). Together with nitricoxide (NO), which is released from the endothelium and transmitshormonal and mechanical signals, it forms the NO/cGMP system. Guanylatecyclases catalyze the biosynthesis of cGMP from guanosine triphosphate(GTP). The representatives of this family disclosed to date can bedivided both according to structural features and according to the typeof ligands into two groups: the particulate guanylate cyclases which canbe stimulated by natriuretic peptides, and the soluble guanylatecyclases which can be stimulated by NO. The soluble guanylate cyclasesconsist of two subunits and very probably contain one heme perheterodimer, which is part of the regulatory center. The latter is ofcentral importance for the mechanism of activation. NO is able to bindto the iron atom of heme and thus markedly increase the activity of theenzyme. Heme-free preparations cannot, by contrast, be stimulated by NO.CO is also able to attach to the central iron atom of heme, but thestimulation by CO is distinctly less than that by NO.

Through the production of cGMP and the regulation, resulting therefrom,of phosphodiesterases, ion channels and protein kinases, guanylatecyclase plays a crucial part in various physiological processes, inparticular in the relaxation and proliferation of smooth muscle cells,in platelet aggregation and adhesion and in the neuronal signaltransmission, and in disorders caused by an impairment of theaforementioned processes. Under pathophysiological conditions, theNO/cGMP system may be suppressed, which may lead for example to highblood pressure, platelet activation, increased cell proliferation,endothelial dysfunction, atherosclerosis, angina pectoris, heartfailure, thromboses, stroke and myocardial infarction.

A possible way of treating such disorders which is independent of NO andaims at influencing the cGMP signal pathway in organisms is a promisingapproach because of the high efficiency and few side effects which areto be expected.

Compounds, such as organic nitrates, whose effect is based on NO have todate been exclusively used for the therapeutic stimulation of solubleguanylate cyclase. NO is produced by bioconversion and activates solubleguanylate cyclase by attaching to the central iron atom of heme. Besidesthe side effects, the development of tolerance is one of the crucialdisadvantages of this mode of treatment.

Some substances which directly stimulate soluble guanylate cyclase, i.e.without previous release of NO, have been described in recent years,such as, for example, 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole(YC-1, Wu et al., Blood 84 (1994), 4226; Mülsch et al., Br. J.Pharmacol. 120 (1997), 681), fatty acids (Goldberg et al, J. Biol. Chem.252 (1977), 1279), diphenyliodonium hexafluorophosphate (Pettibone etal., Eur. J. Pharmcol. 116 (1985), 307), isoliquiritigenin (Yu et al.,Brit. J. Pharmacol. 114 (1995), 1587) and various substituted pyrazolederivatives (WO 98/16223, WO 98/16507 and WO 98/23619).

The stimulators of soluble guanylate cyclase described above stimulatethe enzyme either directly via the heme group (carbon monoxide, nitrogenmonoxide or diphenyliodonium hexafluorophosphate) by interaction withthe central iron of the heme group and a resulting change inconformation which leads to an increase in enzyme activity (Gerzer etal., FEBS Lett. 132(1981), 71), or via a heme-dependent mechanism whichis independent of NO but leads to a potentiation of the stimulatingaction of NO or CO (for example YC-1, Hoenicka et al., J. Mol. Med.(1999) 14; or the pyrazole derivatives described in WO 98/16223, WO98/16507 and WO 98/23619).

The stimulating action of isoliquiritigenin and of fatty acids, such as,for example, arachidonic acid, prostaglandin endoperoxides and fattyacid hydroperoxides on soluble guanylate cyclase claimed in theliterature could not be confirmed (cf., for example, Hoenicka et al., J.Mol. Med. 77 (1999), 14).

If the heme group is removed from soluble guanylate cyclase, the enzymestill has detectable catalytic basal activity, i.e. cGMP is still beingformed. The residual catalytic basal activity of the heme-free enzymecannot be stimulated by any of the known stimulators mentioned above.

Stimulation of heme-free soluble guanylate cyclase by protoporphyrin IXhas been described (Ignarro et al., Adv. Pharmacol. 26 (1994), 35).However, protoporphyrin IX can be considered to be a mimic of theNO-heme adduct, as a consquence of which the addition of protoporphyrinIX to soluble guanylate cyclase would be expected to result in theformation of a structure of the enzyme corresponding to heme-containingsoluble guanylate cyclase stimulated by NO. This is also confirmed bythe fact that the stimulating action of protoporphyrin IX is increasedby the above-described NO-independent but heme-dependent stimulator YC-1(Mülsch et al., Naunyn Schmiedebergs Arch. Pharmacol. 355, R47).

In contrast to the above-described compounds, known from the prior artas stimulators of soluble guanylate cyclase, the compounds according tothe invention are capable of stimulating both the heme-containing andthe heme-free form of soluble guanylate cyclase. Thus, in the case ofthese novel stimulators, stimulation of the enzyme is effected via aheme-independent path, and this is also confirmed by the fact thatfirstly the novel stimulators do not have any synergistic action with NOat the heme-containing enzyme and that secondly the action of thesenovel stimulators cannot be blocked by the heme-dependent inhibitor ofsoluble guanylate cyclase, i.e.1H-1,2,4-oxadiazole-(4,3a)-quinoxalin-1-one (ODQ).

This is a novel therapeutic approach for treating cardiovasculardisorders and other disorders accessible to therapy by influencing thecGMP signal pathway in organisms.

EP-A-0 345 068 describes, inter alia, the aminoalkanecarboxylic acid (1)as an intermediate in the synthesis of GABA antagonists:

WO 93/00359 describes the aminoalkanecarboxylic acid (2) as anintermediate in peptide synthesis and its use as active compound fortreating disorders of the central nervous system:

However, neither of these two publications describes that suchaminoalkane-carboxylic acids may have a stimulating effect, independentof the heme group present in the enzyme, on soluble guanylate cyclase.

Substances having a structure similar to that of the compounds accordingto the invention are furthermore known from WO 01/19776, WO 01/19355, WO01/19780 and WO 01/19778.

The present invention relates to compounds of the general formula (I)

in which

-   -   R¹ is located in the meta- or para-position to the radical W and        represents a radical from the group consisting of H, halogen and        OCF₃;    -   R² represents H or halogen;    -   R³ represents H or halogen;    -   R⁴ represents C₁₋₆-alkyl, C₃₋₈-cycloalkyl, CF₃, OCF₃, F, Cl, OMe        or phenyl, where the phenyl radical may additionally carry a        substituent from the group consisting of halogen, CN,        C₁₋₆-alkoxy, CF₃, C₁₋₆-alkyl;    -   V is located in the ortho- or meta-position to the radical W and        represents O, CH₂O, OCF₃ or O—C₁₋₆-alkyl-O;    -   W represents CH₂ or CH₂CH₂;        and salts, isomers and hydrates thereof.

According to a preferred embodiment, the present invention relates tocompounds of the formula (I) in which

-   -   R¹ is located in the meta-position to the radical W and        represents a radical from the group consisting of H and halogen;    -   R² represents H or halogen;    -   R³ represents H or halogen;    -   R⁴ represents C₁₋₆-alkyl, C₃₋₈-cycloalkyl or phenyl, where the        phenyl radical may additionally carry a substituent from the        group consisting of halogen, CN, C₁₋₆-alkoxy, CF₃, C₁₋₆-alkyl;    -   V is located in the ortho- or meta-position to the radical W and        represents O, CH₂O, OCF₂ or O—C₁₋₆-alkyl-O;    -   W represents CH₂ or CH₂CH₂;        and salts, isomers and hydrates thereof.

According to a particularly preferred embodiment, the present inventionrelates to compounds of the formula (I) in which

-   -   R¹ is located in the meta-position to the radical W and        represents a radical from the group consisting of H, F, Cl and        Br;    -   R² represents H,    -   R³ represents H;    -   R⁴ represents methyl, ethyl, n-propyl, i-propyl, n-butyl,        i-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, or phenyl, where the phenyl radical may additionally        carry a substituent from the group consisting of F, Cl, Br, CN,        methoxy, ethoxy, n-propoxy, i-propoxy, n-butyloxy, i-butyloxy,        t-butyloxy, CF₃, methyl, ethyl, n-propyl, i-propyl, n-butyl,        i-butyl, t-butyl;    -   V is located in the ortho- or meta-position to the radical W and        represents O, CH₂O, OCF₂ or O—C₁₋₆-alkyl-O;    -   W represents CH₂ or CH₂CH₂;        and salts, isomers and hydrates thereof.

According to a further particularly preferred embodiment, the presentinvention relates to compounds of the formula (I) in which

-   -   R¹ is located in the meta-position to the radical W and        represents H;    -   R² represents H;    -   R³ represents H;    -   R⁴ represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,        or phenyl, where the phenyl radical may additionally carry a        substituent from the group consisting of F, Cl, Br, CF₃;    -   V is located in the meta-position to the radical W and        represents O;    -   W represents CH₂;        and salts, isomers and hydrates thereof.

According to a further particularly preferred embodiment, the presentinvention relates to compounds of the formula (I) in which

-   -   R¹ is located in the meta-position to the radical W and        represents H;    -   R² represents H;    -   R³ represents H;    -   R⁴ represents phenyl, where the phenyl radical may additionally        carry a substituent from the group consisting of F, Cl, Br, OMe,        CF₃, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        t-butyl;    -   V is located in the ortho-position to the radical W and        represents OCF₂;    -   W represents CH₂CH₂;        and salts, isomers and hydrates thereof.

According to a further particularly preferred embodiment, the presentinvention relates to compounds of the formula (I) in which

-   -   R¹ is located in the meta-position to the radical W and        represents a radical from the group consisting of H, F, Cl and        Br;    -   R² represents H;    -   R³ represents H;    -   R⁴ represents methyl, ethyl, n-propyl, i-propyl, n-butyl,        i-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, or phenyl, where the phenyl radical may additionally        carry a substituent from the group consisting of F. Cl, Br, CN,        OMe, CF₃, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,        t-butyl;    -   V is located in the ortho-position to the radical W and        represents CH₂O;    -   W represents CH₂CH₂;        and salts, isomers and hydrates thereof.

The compounds according to the invention of the general formula (I) mayalso be in the form of their salts. Mention may generally be made hereof salts with organic or inorganic bases or acids.

Physiologically acceptable salts are preferred for the purposes of thepresent invention. Physiologically acceptable salts of the compoundsaccording to the invention may be salts of the substances according tothe invention with mineral acids, carboxylic acids or sulfonic acids.Particularly preferred examples are salts with hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid,naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid,tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts may likewise be metal or ammonium saltsof the compounds according to the invention having a free carboxylgroup. Particularly preferred examples are sodium, potassium, magnesiumor calcium salts, and ammonium salts derived from ammonia, or organicamines, such as, for example, ethylamine, di- or triethylamine, di- ortriethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine,lysine or ethylenediamine.

The compounds according to the invention may exist in stereoisomericforms which are either like image and mirror image (enantiomers), or notlike image and mirror image (diastereomers). The invention relates bothto the enantiomers or diastereomers and to their respective mixtures.The racermic forms, like the diastereomers, can be separated into thestereoisomerically uniform components in a known manner, for example byoptical resolution or chromatographic separation. Double bonds presentin the compounds according to the invention can be in the cis or transconfiguration (Z or E form).

For the purposes of the present invention, the substituents are, unlessdefined otherwise, generally as defined below:

Alkyl generally represents a straight-chain or branched hydrocarbonradical having 1 to 20 carbon atoms. Examples which may be mentioned aremethyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl,hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl, nonyl, decyl,dodeyl, eicosyl.

Alkoxy generally represents a straight-chain or branched hydrocarbonradical having 1 to 14 carbon atoms which is attached via an oxygenatom. Examples which may be mentioned are methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, pentoxy isopentoxy, hexoxy, isohexoxy,heptoxy, isoheptoxy, octoxy or isooctoxy. The terms “alkoxy” and“alkyloxy” are used synonymously.

Cycloalkyl generally represents a cyclic hydrocarbon radical having 3 to8 carbon atoms. Preference is given to cyclopropyl, cyclopentyl andcyclohexyl. Cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl may bementioned by way of example.

Halogen, for the purposes of the invention, represents fluorine,chlorine, bromine and iodine.

For the purposes of the present invention, the definitions of theradical V are to be understood as meaning that the atom mentioned firstis attached to the phenyl ring which also carries the radical R¹. Thatis, in the case of V=OCF₂, the oxygen atom is attached to the phenylring which also carries the radical R¹.

The present invention furthermore relates to a process for preparing thecompounds of the formula (I), characterized in that compounds of theformula (II)

in which

-   -   R¹, V and W are as defined in claim 1 and    -   L, if V is O, represents methyl or otherwise represents a        radical of the formula    -    where R², R³ and R⁴ are as defined above,        are reacted with a C₁₋₆-alkyl 4-formylbenzoate in an organic        solvent, if appropriate with heating and simultaneous or        subsequent addition of a reducing agent, to give compounds of        the formula (III)        in which R¹, V, W and L are as defined above and Q represents a        C₁₋₆-alkyl radical,        then—if appropriate with prior cleavage of the ether to give the        free hydroxyl group, if V represents O and L represents        methyl—reacted with a C₁₋₆-alkyl ω-halovalerate in an organic        solvent in the presence of a base with heating to give compounds        of the formula (IV)        in which R¹, V, W, and Q are as defined above, Q′ represents a        C₁₋₆-alkyl radical and L represents H—if V is O—or a radical of        the formula II-A,        then—if V is O and L represents H—reacted with a compound of the        formula IV-A in an organic solvent with heating        where R² and R³ are as defined in claim 1 and X and X′ each        represent halogen,        followed by palladium-catalyzed substitution of the radical X        with a benzene boronic acid derivative to give compounds of the        formula (V)        and subsequent hydrolysis of the compounds of the formula (IV)        or (V) under alkaline conditions to give the compounds of the        formula (I).

The bases which are preferably used for the processes according to theinvention include basic compounds which are customarily used for basicreactions. Preference is given to using alkali metal hydrides, such as,for example, sodium hydride or potassium hydride, or alkali metalalkoxides, such as sodium methoxide, sodium ethoxide, potassiummethoxide, potassium ethoxide or potassium t-butoxide, or carbonates,such as sodium carbonate, cesium carbonate or potassium carbonate, oramides, such as sodium amide or lithium diisopropylamide, ororganolithium compounds, such as phenyllithium, butyllithium ormethyllithium, or sodium hexamethyldisilazane.

Solvents which are preferred for converting the compounds of the formula(II) into the compounds of the formula (III) are customary organicsolvents which do not change under the reaction conditions. Preferenceis given to using, for the process according to the invention, ethers,such as diethyl ether, butyl methyl ether, dioxane, tetrahydrofuran,glycol dimethyl ether or diethylene glycol dimethyl ether, orhydrocarbons such as benzene, toluene, xylene or petroleum ether, oralcohols, such as methanol or ethanol, or halogenated hydrocarbons, suchas carbon tetrachloride, chloromethane or dichloromethane. It is, ofcourse, also possible to use mixtures of the solvents mentioned above.Preference according to the invention is given to using ethanol,methanol, dichloromethane or toluene.

Initially, the compounds of the formula (II) are reacted with aC₁₋₆-alkyl 4-formylbenzoate to give a Schiff base, which is then reducedwith customary reducing agents, such as, for example, NaBH₄, H₂/Pd/C,etc., or reacted directly under the conditions of a reductive alkylationin the presence of a reducing agent, such as, for example, H₂/Pd/C,NaCNBH₃, NaH(OAc)₃ (cf. Patai, Ed., The Chemistry of the Carbon-NitrogenDouble Bond, pp. 276-293 and the literature cited therein). Here,depending on the nature of the starting material, the reaction can becarried out at room temperature or has to be heated at from 50 to 110°C. for several hours up to several days. The reaction can be carried outat atmospheric pressure, elevated or reduced pressure (for example inthe range of from 0.5 to 5 bar). In general, the reaction is carried outat atmosphere pressure. C₁₋₆-Alkyl 4-formylbenzoates are commerciallyavailable, known from the literature, or can be synthesized analogouslyto processes known from the literature (cf., for example, J. Med. Chem.1989, 32, 1277; Chem. Ber. 1938, 71, 335; Bull. Soc. Chim. Fr. 1996,123, 679, WO 96/11902; DE-2209128; Synthesis 1995; 1135; Bull. Chem.Soc. Jpn. 1985, 58, 2192, Synthesis 1983, 942; J. Am. Chem. Soc. 1992,114, 8158).

The conversion of the compounds of the formula (III) into the compoundsof the formula (IV) can preferably be carried out in acetonitrile orbutyronitrile, in each case by reacting the compounds (II) and (III),(IV) and (V) and (VI) and (VII), respectively, in the presence of abase, such as sodium carbonate, Et₃N, DABCO, K₂CO₃, KOH, NaOH or NaH. Ingeneral, the reaction can be carried out in a temperature range of from−20° C. to +90° C., preferably from 0° C. to +70° C. The reaction can becarried out at atmospheric pressure, elevated or reduced pressure (forexample in a range of from 0.5 to 5 bar). In general, the reaction iscarried out at atmospheric pressure. However, suitable solvents are, inprinciple, the solvents mentioned above for the conversion of thecompounds of the formula (II) into compounds of the formula (III).According to the invention, the alkyl ω-halovalerate used is preferablythe corresponding methyl ω-bromovalerate. Alkyl ω-halovalerates arecommercially available, known from the literature or can be synthesizedaccording to processes known from the literature (cf., for example, J.Chem. Soc. 1958, 3065).

If V is O and L is methyl, the methoxy group present should be convertedinto the free hydroxyl group prior to the reaction of the correspondingcompound of the formula (II) with the alkyl ω-halovalerate. This can becarried out in a known manner (cf., for example, T. W. Greene, P. G. M.Wuts, Protective Groups in Organic Synthesis, second edition, New York,1991). The methyl group can be removed with formation of the phenol, forexample, using boron tribromide in methylene chloride at from −70 to 20°C., using trimethylsilyl iodide in chloroform at 25-50° C. or usingsodium ethylthiolate in DMF at 150° C. According to the invention, thereaction with boron tribromide is preferred.

The compounds of the formula (IV) are then converted into the compoundsof the formula (I) by hydrolysis of the ester functions, giving the freecarboxyl groups, for example by addition of aqueous solutions of strongacids, such as, for example, HCl or H₂SO₄, or strong bases, such as, forexample, NaOH, KOH or LiOH. The reaction can be carried out in one ofthe organic solvents mentioned above, in water or in mixtures of organicsolvents or mixtures of organic solvents with water. Preferenceaccording to the invention is given, for example, to carrying out thereaction in a mixture of water and methanol or dioxane. The reaction cangenerally be carried out in a temperature range of from −20° C. to +90°C., preferably of from 0° C. to +90° C. The reaction can be carried outunder atmospheric pressure, elevated or reduced pressure (for example ina range of from 0.5 to 5 bar). In general, the reaction is carried outunder atmospheric pressure.

If, in the compounds of the formula (IV), V is O and L is H, thehydrolysis of the ester functions described above is preceded by areaction with the compounds of the formula (IV-A). This is anucleophilic substitution of a leaving group X′ in the compound of theformula (IV-A) by the hydroxyl function of the compound of the formula(IV). Suitable leaving groups X′ are, for example: halogen, tosylate,mesylate or a hydroxyl function activated by reagents such asdiisopropyl azodicarboxylate/PPh₃ (Mitsonobu reaction). Preferably, X′is halogen, particularly preferably Br. This reaction can preferably becarried out in dimethylformamide (DMF) by reacting the compounds (IV)and (IV-A) in the presence of a base, such as sodium carbonate,potassium carbonate, Et₃N, DABCO, K₂CO₃, KOH, NaOH or preferably NaH.The reaction can generally be carried out in a temperature range of from−20° C. to +90° C., preferably of from 0° C. to +90° C. The reaction canbe carried out under atmospheric pressure, elevated or reduced pressure(for example in a range of from 0.5 to 5 bar). In general, the eractionis carried out under atmospheric pressure.

The compounds of the formula (IV-A) can be obtained from compounds whichare commercially available, known from the literature or synthesizableanalogously to processes known from the literature (cf., for example, J.prakt. Chem. 1960, 341; Farmaco Ed. Sci. 1956, 378; Eur. J. Med. Chim.Ther. 1984, 19, 205; Bull. Soc. Chim. Fr. 1951, 97. Liebigs Ann. Chem.1954, 586, 52; EP-A-0 334 137) by NBS bromination of the difluoromethylgroup analogously to processes known from the literature (cf., forexample, Monatsh. Chem. 1996, 127(2), 201-217; J. Med. Chem. 1992, 35,368; J. heterocycl. Chem. 24 (1987), N3, 725-731; Synth. Commun. 1996,26(15), 2803-2809).

The resulting compound, which contains a substitutable group X, is thenprepared by reaction with a benzeneboronic acid derivative in thepresence of a palladium compound and, if appropriate, a reducing agentand further additives in basic medium. Formaly, the reaction is areductive coupling as described, for example, in L. S. Hegedus,Organometallics in Synthesis, M. Schlosser, Ed., Wiley & Sons, 1994. Thesubstitutable group X used can, for example, be a halogen radical, suchas Br or I, or a customary leaving group, such as, for example, atriflate radical. Preference according to the invention is given to ahalogen radical, in particular to Br. The palladium compound used can bea palladium (II) compound, such as, for example, Cl₂Pd(PPh₃)₂ orPd(OAc)₂, or a palladium(0) compound, such as, for example, Pd(PPh₃)₄ orPd₂(dba)₃. If required, a reducing agent, such as, for example,triphenylphosphine, or other additives, such as, for example, Cu(I)Br,NBu₄NCl, LiCl or Ag₃PO₄, can additionally be added to the reactionmixture (cf. T Jeffery, Tetrahedron lett. 1985, 26, 2667-2670; T.Jeffery, J. Chem. Soc. Chem. Commun. 1984, 1287-1289; S. Bräse, A.deMejiere in “Metal-catalyzed cross-coupling reactions”, Ed. F.Diederich, P. J. Stang, Wiley-VCH, Weinheim 1998, 99-166). The reactionis carried out in the presence of a customary base, such as, forexample, Na₂CO₃, NaOH or triethylamine. Suitable solvents are theorganic solvents mentioned above, ethers, such as, for example,1,2-dimethoxyethane, being particularly preferred. In general, thereaction can be carried out in a temperature range of from −20° C. to+90° C., preferably of from 0° C. to +90° C. The reaction can be carriedout under atmospheric pressure, elevated or reduced pressure (forexample in a range of from 0.5 to 5 bar). In general, the reaction iscarried out at atmospheric pressure.

Benzeneboronic acids are commercially available, known from theliterature, or can be synthesized analogously to processes known fromthe literature (cf., for example, J. Chem. Soc. C 1966, 566. J. Org.Chem., 38, 1973, 4016).

The compounds of the formula (V) prepared in this manner can then behydrolyzed as described above to give the compounds of the formula (I).

The compounds of the formula (II) are obtainable by different routes ormay even be commercially available. Thus, compounds of the formula (II)where V is CH₂O can be obtained by esterifying commercially availablemethylbenzoic acids, NBS bromination of the methyl group analogously toprocesses known from the literature (cf., for example, Manatsh. Chem.1996, 127(2). 201-217; J. Med. Chem. 1992, 35, 368; J. heterocycl. Chem.24 (1987), N3, 725-731; Synth. Commun. 1996, 26(15), 2803-2809) to givethe corresponding bromomethyl compounds, subsequent substitution of thebromine group introduced by the phenolic OH group of a commerciallyavailable phenol compound in an organic solvent, such as acetonitrile,in the presence of a base, such as, for example, potassium carbonate,and conversion of the ester group by reduction with customary reducingagents, such as, for example, LiAlH₄, conversion into the correspondingbenzyl halide using, for example, SOCl₂ or using carbontetrabromide/triphenylphosphine in an organic solvent, such as diethylether, nucleophilic substitution with a cyanide, such as, for example,NaCN or trimethylsilyl cyanide, and reduction of the nitrile function bymethods known from the literature, such as, for example, BH₃.THF,BH₃.S(CH₃)₂ or LiAlH₄/AlCl₃.

If V is O, the compounds of the formula (II) can be prepared fromhalobenzonitriles which are commercially available known from theliterature or synthesizable analogously to processes known from theliterature (cf., for example, Chem. Pharm. Bull. 31, 10, 1983,3424-3445; Bull. Chem. Soc. Fr. <II>, 1979, 241-248; Chem. Ber. 80,1947, 469-472, J. Chem. Soc. 1933, 489-493) by reaction with acommercially available phenol compound in an organic solvent, such aspyridine, in the presence of a base, such as, for example, potassiumcarbonate, and in the presence of CuI, under an atmosphere of protectivegas and with heating, followed by reduction of the nitrile function asdescribed above.

The compounds of the general formula (I) according to the invention showa valuable range of pharmacological effects which could not have beenpredicted.

The compounds of the general formula (I) according to the invention,bring about vasorelaxation and an inhibition of platelet aggregation andlead to a reduction in blood pressure and an increase in the coronaryblood flow. These effects are mediated by direct stimulation of solubleguanylate cyclase and an intracellular increase in cGMP.

They can therefore be employed in medicaments for the treatment ofcardiovascular disorders such as, for example, for the treatment of highblood pressure and heart failure, stable and unstable angina pectoris,peripheral and cardiac vascular disorders, of arrhythmias, for thetreatment of thromboembolic disorders and ischemias such as myocardialinfarction, stroke, transitory and ischemic attacks, disturbances ofperipheral blood flow, prevention of restenosis such as afterthrombolysis therapies, percutaneous transluminal angioplasties (PTAs),percutaneous transluminal coronary angioplasties (PTCAs), bypass and forthe treatment of arteriosclerosis, fibrotic disorders, such as fibrosisof the liver or pulmonary fibrosis, asthmatic disorders and diseases ofthe urogenital system such as, for example, prostate hypertrophy,erectile dysfunction, female sexual dysfunction and incontinence andalso for the treatment of glaucoma.

The compounds of the general formula (I) described in the presentinvention, are also active compounds suitable for controlling centralnervous system diseases characterized by disturbances of the NO/cGMPsystem. They are suitable in particular for removing cognitive deficits,for improving learning and memory performances and for treatingAlzheimer's disease. They are also suitable for treating disorders ofthe central nervous system such as states of anxiety, tension anddepression, CNS-related sexual dysfunctions and sleep disturbances, andfor controlling pathological disturbances of the intake of food,stimulants and addictive substances.

The active compounds are furthermore also suitable for regulatingcerebral blood flow and thus represent effective agents for controllingmigraine.

They are also suitable for the prophylaxis and control of the sequelaeof cerebral infarction (apoplexia cerebri) such as stroke, cerebralischemias and craniocerebral trauma. The compounds according to theinvention of the general formula (I) can likewise be employed forcontrolling states of pain.

In addition, the compounds according to the invention have ananti-inflammatory effect and can therefore be employed asanti-inflammatory agents.

As a particular and surprising feature, the compounds of the presentinvention have a long duration of action, which was unexpected.

Vasorelaxant Effect In Vitro

Rabbits are anesthetized or killed by intravenous injection ofthiopental sodium (about 50 mg/kg) and exsanguinated. The arteriasaphena is removed and divided into rings 3 mm wide. The individualrings are in each case mounted on a pair of hooks of triangular shape,open at the end and made of special wire (Remanium®) having a diameterof 0.3 mm. Under pretension, each ring is introduced into a 5 ml organbath containing carbogen-gassed Krebs-Henseleit solution at 37° C. withthe following composition (mM): NaCl: 119; KCl: 4.8; CaCl₂×2H₂O: 1;MgSO₄×7H₂O: 1.4; KH₂PO₄: 1.2; NaHCO₃: 25; glucose: 10; bovine serumalbumin: 0.001%. The force of contraction is detected with Statham UC2cells, amplified and digitized via A/D converters (DAS-1802 HC, KeithleyInstruments, Munich) and recorded in parallel on chart recorders.Contractions are generated by adding phenylephrine.

After several (generally 4) control cycles, the substance to beinvestigated is added in each further run in increasing dosage in eachcase, and the height of the contraction reached under the influence ofthe test substance is compared with the height of the contractionreached in the last preceding run. The concentration necessary to reducethe height of the control value by 50% (IC₅₀) is calculated from this.The standard application volume is 5 μl. The DMSO content in the bathsolution corresponds to 0.1%.

The results are shown in table 1:

TABLE 1 Vasorelaxant effect in vitro Example IC₅₀ (nM) 2 55 3 36 6 0.04112  0.4 17  0.26Stimulation of Recombinant Soluble Guanylate Cyclase (sGC) In Vitro

The investigations of the stimulation of recombinant soluble guanylatecyclase (sGC) and the compounds according to the invention with andwithout sodium nitroprusside and with and without the heme-dependent sGCinhibitor 1H-1,2,4-oxadiazole-(4,3a)-quinoxalin-1-one (ODQ) were carriedout according to the method described in detail in the followingliterature reference: M. Hoenicka, E. M. Becker, H. Apeler, T.Sirichoke, H. Schroeder, R. Gerzer and J-P. Stasch: Purified solubleguanylyl cyclase expressed in a baculovirus/Sf9 system: stimulation byYC-1, nitric oxide, and carbon oxide. J. Mol. Med. 77 (1999): 14-23.

The heme-free guanylate cyclase was obtained by adding Tween 20 to thesample buffer (final concentration 0.5%).

Activation of sGC by a test substance is stated as n-fold stimulation ofbasal activity.

Investigation of the Antifibrotic Action of the Substances In Vivo

Method

The antifibrotic action of the substances was investigated using themodel of the porcine serum-induced rat liver fibrosis. Treatment withheterologous serum, for example porcine serum in rats, is a methodfrequently used in the literature for inducing fibrosis of the liverwith subsequent cirrhosis which, in contrast to other models, causesonly minimal damage and inflammation of the parenchyma cells of theliver (Bhunchet, E. and Wake, K. (1992): Role of mesenchymal cellpopulations in porcine serum-induced rat liver fibrosis. Hepatology 16:1452-1473). Female Sprague Dawley rats were treated 2× per week with 0.5ml/animal of sterile porcine serum (Sigma) i.p., control animals weretreated with sterile physiological saline (2× per week 0.5 ml/animali.p.). The treatment with test substance (1× per day in 5 ml/kg of p.o.solvent comprising 20% Cremophor, 10% Transcutol and 70% H₂O) wascarried out in parallel to the treatment with porcine serum. After sevenweeks of treatment, the animals were killed and the livers were removedin order to quantify the collagen content.

For the histological examination of the liver tissue, standardizedtransverse tissue cylinders (about 10×2 mm) were punched out of theright anterior lobe of the liver. For the detection of scar collagencaused by liver fibrosis, frozen sections were stained with 0.1%strength Pikrosirius Red solution.

Fast Green was used as counterstain to enhance contrast. In eachsection, the extent of liver fibrosis was determined as a percentage ofthe area stained by Pikrosirius Red of the total area measured. Theparameters of the video microscopic stain detection were standardizedand kept constant for the entire experiment. 64 fields of a standardizedgrid of 31 mm² were measured using a final amplification of 100. Forsemiautomatic morphometry, a Leica Quantimed 500MC (Leica Germany) wasused.

To determine OH-proline according to Prockop and Udenfried (Prockop, D.J. and Udenfried, S. A. (1960): A specific method for the analysis ofhydroxyproline in tissues and urine. Anal. Biochem. 1: 228-239), in eachcase 50-100 mg of liver tissue were dried and boiled with 6N HCl forabout 17 hours. The acid was evaporated in a vacuum drying oven and theresidue was then dissolved in 5 ml of distilled water and filtered. 200μl of the filtered solution were incubated at room temperature with 200μl of ethanol and 200 μl of oxidation solution (7% strength aqueouschloramine T hydrate solution, diluted 1:4 with acetate/citrate bufferpH 6.0) for 25 min. 400 μl of Erlich's reagent (12 g of4-dimethylaminobenzaldehyde in 20 ml of ethanol+2.74 ml of concentratedsulfuric acid in 20 ml of ethanol) were then added. After 3 hours ofincubation at 35° C., absorption at 573 nm was measured. AqueousOH-proline solutions (Sigma) were used for the calibration curve. TheOH-proline content of the liver samples was calculated in mg per g ofliver dry weight.

Results

The OH-proline values agreed very well with the results of themorphometric fibrosis measurement: without simultaneous administrationof substance, the porcine serum treatment resulted in a pronouncedaccumulation of collagen in the liver. The formation of these collagendeposits is reduced by treatment with the substances in a dose-dependentmanner.

The present invention includes pharmaceutical preparations which, inaddition to non-toxic, inert, pharmaceutically acceptable carriers,comprises the compounds according to the invention, in particular thecompounds of the general formula (I), and processes for preparing thesepreparations.

The active compound, if appropriate in one or more of the carrierslisted above, can also be present in microencapsulated form.

The therapeutically effective compounds, in particular the compounds ofthe general formula (I), should be present in the pharmaceuticalpreparations detailed above in a concentration of about 0.1 to 99.5,preferably of about 0.5 to 95, % by weight of the complete mixture.

The pharmaceutical preparations detailed above may, apart from thecompounds according to the invention, in particular the compounds of thegeneral formula (I), also contain other active pharmaceuticalingredients.

It has generally proved to be advantageous both in human and inveterinary medicine to administer the active compound(s) according tothe invention in total amounts of about 0.5 to about 500, preferably 5to 100, mg/kg of body weight every 24 hours, where appropriate in theform of a plurality of single doses, to achieve the desired results. Asingle dose contains the active compound(s) according to the inventionpreferably in amounts of about 1 to about 80, in particular 3 to 30,mg/kg of body weight.

Below, the present invention is illustrated in more detail usingnon-limiting preferred examples. Unless indicated otherwise, allquantities are stated in percent by weight.

EXAMPLES

Abbreviations:

RT: room temperature EA: ethyl acetate BABA: n-butylacetate/n-butanol/glacial acetic acid/phosphate buffer pH 6 (50:9:25.15;org. phase)Mobile Phases for Thin-layer Chromatograhy:

T1 E1: toluene - ethyl acetate (1:1) T1 EtOH1: toluene - methanol (1:1)C1 E1: cyclohexane - ethyl acetate (1:1) C1 E2: cyclohexane - ethylacetate (1:2)Starting Materials

Ex. I 3-(4-Cyclohexylphenoxy)benzonitrile

Under argon, 1.2 g (6.81 mmol) of 4-cyclohexylphenol, 7.44 g (40.85mmol) of 3-bromobenzonitrile, 1.3 g (6.81 mmol) of copper(I) iodide and1.88 g (13.62 mmol) of potassium carbonate are suspended in 24 ml ofpyridine and stirred at 140° C. for 15 h. After cooling, the reactionmixture is filtered through kieselguhr, the filter cake is washed withdichloromethane and the filtrate is concentrated using a rotaryevaporator. The resulting residue is taken up in ethyl acetate andwater, and 2-N-HCl is added. The resulting precipitate is filtered offthrough kieselguhr. The resulting filtrate is then extracted twice with2-N-HCl and with sat. NaCl solution. After drying over MgSO₄ and removalof the solvent by evaporation, the product is purified by columnchromatography (silica gel, cyclohexane/ethyl acetate 25:1). This gives876 mg (3.16 mmol, 44% yield) of a colorless oil.

R_(f) (cyclohexane/ethyl acetate, 2:1): 0.71. ¹H-NMR (300 MHz, CDCl₃,δ/ppm): 7.42-7.32 (2H, m), 7.29-7.15 (4H, m), 6.95 (2H, d), 2.35 (1H,m), 1.96-1.60 (5H, m), 1.50-1.25 (5H, m). MS (DCl, NH₃: 572 (2M+NH₄ ⁺),317 (M+N₂H₇ ⁺), 295 (M+NH₄ ⁺), 277 (M⁺).

Ex. II 3-(4-Cyclohexylphenoxy)benzylamine

At 0° C., a solution of 600 mg (2.16 mmol) of3-(4-cyclohexylphenoxy)benzonitrile from Ex. I in 6 ml of anhydrousdiethyl ether is added dropwise to 4.32 ml (4.32 mmol) of a 1-molarsolution of LiAlH₄ in THF. Over a period of 4 h, the reaction mixture iswarmed to room temperature, and 10 ml of a sat. solution of NH₄Cl arethen added carefully, the mixture is diluted with ether and the organicphase is removed. The organic phase is washed successively with waterand a sat. solution of NaCl, dried over MgSO₄ and, after filtration,freed from the solvent. This gives 573 mg (1.81 mmol, purity 88.82%, 84%yield) of 3-(4-cyclohexylphenoxy)benzylamine.

R_(f) (dichloromethane/methanol 9/1): 0.13 ¹H-NMR (400 MHz, CDCl₃,δ/ppm): 7.26 (2H, d), 7.16 (2H, d), 7.05-6.85 (4H, m), 3.86 (2H, s),2.51 (1H, m), 1.93-1.79 (4H, m), 1.70-1.55 (2H, m), 1.48-1.31 (4H, m).MS (EI): 280 (M⁺).

Ex. III Methyl 4-({[3-(4-cyclohexylphenoxy)benzyl]amino}methyl)benzoate

Under argon, 806 mg (3.80 mmol) of sodium triacetoxyborohydride areadded to a solution of 535 mg (1.90 mmol) of3-(4-cyclohexylphenoxy)benzylamine from Ex. II and 312 mg (1.90 mmol) ofmethyl 4-formylbenzoate in 5 ml of dichloromethane, and the mixture isstirred at room temperature overnight. 10 ml of a sat. solution ofNaHCO₃ are then added carefully to the reaction mixture, the mixture isdiluted with dichloromethane and the organic phase is removed. Theorganic phase is dried over MgSO₄ and concentrated using a rotaryevaporator. This gives 429 mg (1 mmol) of methyl4-({[3-(4-cyclohexylphenoxy)benzyl]amino}methyl)benzoate as a colorlessoil.

R_(f) (dichloromethane/methanol 10:1): 0.56. ¹H-NMR (300 MHz CDCl₃,δ/ppm): 7.99 (2H, d), 7.40 (2H, d), 7.28 (1H, d), 7.18 (2H, d),7.08-6.99 (2H, m), 6.97-6.87 (3H, m), 3.91 (3H, s), 3.85 (2H, s), 3.78(2H, s), 2.51 (1H, m), 1.93-1.70 (5H, m), 1.50-1.32 (5H, m). MS (ESI):430 (M+H⁺).

Ex. IV Methyl4-{[[3-(4-cyclohexylphenoxy)benzyl](5-methoxy-5-oxopentyl)amino]methyl}benzoate

207 mg (1.95 mmol) of anhydrous potassium carbonate are added to asolution of 381 mg (0.89 mmol) of methyl4-({[3-(4-cyclohexylphenoxy)benzyl]amino}methyl)benzoate from Ex. IIIand 140 μl (0.98 mmol) of methyl 5-bromovalerate in 3.3 ml ofacetonitrile, and the mixture is heated at reflux for 48 hours. Themixture is then concentrated, taken up in ethyl acetate and washed withwater. After drying over Na₂SO₄, filtration and concentration, theproduct is purified by column chromatography (silica gel,cyclohexane/ethyl acetate 5:1). This gives 389 mg (0.71 mmol, 78% yield)of a colorless oil.

R_(f) (dichloromethane): 0.09. ¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 7.87(2H, d), 7.39 (2H, d), 7.30 (1H, t), 7.23 (2H, d), 7.04 (1H, m),6.95-6.83 (4H, m), 3.82 (3H, s), 3.60 (5H, s), 3.55 (4H, m), 2.51 (1H, mpartially obscured by DMSO), 2.19 (2H, t), 1.90-1.73 (7H, m), 1.70-1.53(2H, m), 1.45-1.32 (5H, m). MS (ESI): 544 (M+H⁺).

Ex. V 1-Bromo-4-[bromo(difluoro)methyl]benzene

Under exclusion of oxygen, a solution of 14.0 g (67.63 mmol) of1-bromo-4-(difluoromethyl)benzene (CAS 51776-71-7) and 25.3 g (142 mmol)of N-bromosuccinimide (NBS) in 190 ml of carbon tetrachloride isirradiated using a daylight lamp. During the radiation, the solventreaches its boiling point. The mixture is irradiated under reflux for 24hours. The mixture is then allowed to cool to room temperature, andprecipitated succinimide is filtered off. Another 25 g of NBS are addedto the filtrate, and the mixture is once more, under exclusion ofoxygen, irradiated under reflux for 24 hours. After cooling, the mixtureis again filtered and the filtrate is evaporated to dryness. This gives18 g of a dark orange oil which is purified by vacuum distillation at 13torr. This gives 12.7 g (44.4 mmol, 66% yield) of a colorless oil.

Boiling point (13 torr): 90-92° C. ¹H-NMR (300 MHz, DMSO-d₆, δ/ppm):7.79 (2H, d), 7.63 (2H, d). MS (ESI): 205/207 (M−Br⁻).

Ex. VI Methyl 4-({[2-(2-methoxyphenyl)ethyl]amino}methyl)benzoate

A solution of 92.08 g (0.597 mol) of 2-methoxyphenethylamine and 98.0 g(0.597 mol) of methyl 4-formylbenzoate in 2 l of ethanol is heated atreflux for 2 hours. The solvent is then removed under reduced pressureand the resulting residue is dissolved in 1 l of methanol. A total of46.14 g of solid NaBH₄ are added a little at a time. After two hours ofstirring at room temperature, the mixture is poured into water andextracted with ethyl acetate. The organic extract is washed withsaturated sodium chloride solution and dried over Na₂SO₄. Afterfiltration, the solvent is removed under reduced pressure. This gives167.7 g (0.559 mol, 77% yield) of a colorless oil which is used withoutfurther purification for the next step. ¹H-NMR (200 MHz, DMSO-d₆,δ/ppm): 7.90 (2H, d), 7.45 (2H, d), 7.17 (1H, t), 7.12 (1H, d), 6.92(1H, d), 6.83 (1H, t), 3.83(3H, s), 3.78 (2H, s), 3.73 (3H, m),2.75-2.63 (4H, m). MS (DCI, NH₃): 300 (M+H⁺).

Ex. VII Methyl 4-({[2-(2-hydroxyphenyl)ethyl]amino}methyl)benzoatehydrobromide

At 0° C., 661.4 ml (0.66 mol) of a 1-molar solution of boron tribromidein dichloromethane are added to a solution of 60.0 g (0.2 mol) of methyl4-({[2-(2-methoxyphenyl)ethyl]amino}methyl)benzoate from Ex. VI in 200ml of dichloromethane. The mixture is stirred at 0° C. for one hour. 300ml of methanol are then added, and the mixture is heated at reflux for18 hours. On cooling, the product precipitates out and is filtered off.Further product is obtained by concentrating the mother liquor. Thecollected product fractions are washed with ether. This gives 45.04 g(0.16 mol, 56% yield) of a white crystalline solid.

R_(f) (dichloromethane/methanol 10:1): 0.54. ¹H-NMR (300 MHz, DMSO-d₆,δ/ppm): 9.58 (1H, broad), 9.02 (2H, broad), 8.03 (2H, d), 7.68 (2H, d),7.09 (1H, d), 7.07 (1H, t), 6.82 (1H, d), 6.77 (1H, t), 4.29 (2H, s),3.89 (3H, s), 3.18-3.10 (2H, m), 2.94-2.88 (2H, m). MS (ESI): 286(M+H⁺).

Ex. VIII Methyl4-{[[2-(2-hydroxyphenyl)ethyl](5-methoxy-5-oxopentyl)-amino]methyl}benzoate

3.0 g (8.19 mmol) of methyl4-({[2-(2-hydroxyphenyl)ethyl]amino}methyl)benzoate hydrobromide fromEx. VII, 1.3 ml (9.83 mmol) of methyl 5-bromovalerate and 1.74 g (16.38mmol) of anhydrous sodium carbonate in 20 ml of acetonitrile are heatedat reflux for three days. The mixture is then concentrated to drynessand the residue is taken up in ethyl acetate and washed with water andsaturated sodium chloride solution. After drying over Na₂SO₄, themixture is filtered and concentrated. The product is purified by flashchromatography (silica gel, cyclohexane/ethyl acetate 7:3). This gives2.2 g (5.51 mmol. 67% yield) of a pale yellow oil.

R_(f) (cyclohexane/ethyl acetate 2:1): 0.28. ¹H-NMR (300 MHz, DMSO-d₆,δ/ppm): 9.57 (1H, s broad), 7.89 (2H, d), 7.43 (2H, d), 6.99 (1H, d),6.98 (1H, t), 6.72 (1H, d), 6.67 (1H, t), 3.83 (3H, s), 3.69 (2H, s),3.57 (3H, s), 2.71-2.66 (2H, m), 2.62-2.55 (2H, m), 2.45 (2H, t), 2.23(2H, t), 1.51-1.40 (4H, m). MS (DCI, NH₃): 400 (M+H⁺), 252.

Ex. IX Methyl4-{[(2-{2-[(4-bromophenyl)(difluoro)methoxy]phenyl}ethyl(5-methoxy-5-oxopentyl)amino]methyl}benzoate

240 mg (6.0 mmol) of a 60% strength suspension of NaH in mineral oil areinitially charged in 60 ml of anhydrous DMF, and at 0° C., a solution of2.0 g (5.0 mmol) of methyl4-{[[2-(2-hydroxyphenyl)ethyl](5-methoxy-5-oxopentyl)amino]methyl}benzoatefrom Ex. VIII in 1 ml of DMF is added. The mixture is allowed to warm toroom temperature. After 30 minutes, 1.59 g (5.0 mmol) of1-bromo-4-[bromo(difluoro)methyl]benzene from Ex. 5, dissolved in 1 mlof DMF, are added dropwise, and the mixture is heated at 70° C. After 15hours, the mixture is allowed to cool to room temperature, diluted withdichloromethane and washed successively with aqueous 5% strength NaH₂PO₄solution and saturated sodium chloride solution. Drying over Na₂SO₄. Theproduct is purified by flash chromatography (silica gel,cyclohexane/ethyl acetate gradient 20:1→5:1). This gives 1.42 g (2.35mmol, 47% yield) of a viscous yellow oil.

R_(f) (cyclohexane/ethyl acetate 2:1): 0.39. ¹H-NMR (300 MHz, DMSO-d₆,δ/ppm): 7.82 (2H, d), 7.76 (2H, d), 7.65 (2H, d), 7.33 (2H, d),7.30-7.18 (4H, m), 3.86 (3H, s), 3.59 (2H, s), 3.57 (3H, s), 2.77 (2H,dd), 2.58 (2H, dd), 2.48 (2H, t), 2.14 (2H, t), 1.43-1.28 (4H, m). MS(DCI, NH₃): 604/606 (M+H⁺).

Ex. X Methyl4-{[[(2-(2-difluoro[4′-(trifluoromethyl)-1,1′-biphenyl-4-yl]-methoxy}phenyl)ethyl](5-methoxy-5-oxopentyl)amino]methyl}benzoate

0.75 ml of a 2-molar aqueous sodium carbonate solution is added to asolution of 300 mg (0.50 mmol) of methyl4-{[(2-{2-[(4-bromophenyl)(difluoro)methoxy]phenyl}ethyl(5-methoxy-5-oxopentyl)amino]methyl}benzoatefrom Ex. IX, 103.4 mg (0.55 mmol) of 4-trifluoromethylbenzeneboronicacid and 17.2 mg (0.01 mmol) of tetrakis(triphenylphosphino)palladium(0)in 5 ml of 1,2-dimethoxyethane, and the mixture is, under argon, heatedat reflux for 18 hours. The mixture is then diluted with ethyl acetateand washed successively with 5% strength NaH₂PO₄ solution, water andsaturated sodium chloride solution. Drying over Na₂SO₄. The product ispurified by flash chromatography (silica gel, cyclohexane/ethyl acetategradient 30:1→1:1). This gives 260 mg (0.39 mmol, 78% yield) of a yellowoil.

R_(f) (cyclohexane/ethyl acetate 4:1): 0.28. ¹H-NMR (300 MHz, DMSO-d₆,δ/ppm): 7.95-7.79 (10H, m), 7.37-7.19 (6H, m), 3.79 (3H, s), 3.60 (2H,s), 3.49 (3H, s), 2.81 (2H, dd), 2.61 (2H, dd), 2.40 (2H, t), 2.12 (2H,t), 1.41-1.30 (4H, m). MS (ESI): 670 (M+H⁺).

Ex. XI Methyl 2-[(4-cyclohexylphenoxy)methyl]-5-fluorobenzoate

2.14 g (12.14 mmol) of 4-cyclohexylphenol and 3.0 g (12.14 mmol) ofmethyl 2-(bromomethyl)-5-fluorobenzoate (CAS 138786-65-9) are, togetherwith 2.5 g (18.21 mmol) of anhydrous potassium carbonate, heated atreflux in 20 ml of acetonitrile. After three hours, the mixture isevaporated to dryness using a rotary evaporator. The residue is taken upin ether and washed successively with water and saturated sodiumchloride solution. Drying is carried out over Na₂SO₄. The crude productis purified by flash chromatography (silica gel, cyclohexane/ethylacetate 80:1). This gives 3.37 g (9.84 mmol, 81% yield) of a colorlessoil.

R_(f) (cyclohexane/ethyl acetate 9:1): 0.56. ¹H-NMR (200 MHz, DMSO-d₆,δ/ppm): 7.72-7.43 (3H, m), 7.13 (2H, d), 6.88 (2H d), 5.32 (2H, s), 3.81(2H, s), 2.51-2.36 (1H, m), 1.80-1.62 (5H, m), 1.46-1.20 (5H, m). MS(ESI): 707 (2M+Na⁺), 365 (M+Na⁺).

Ex. XII {2-[(4-Cyclohexylphenoxy)methyl]-5-fluorophenyl}methanol

6.6 ml (6.6 mmol) of a 1-molar solution of LiAlH₄ in ether are initiallycharged and diluted with a further 20 ml of ether. Without cooling ofthe reaction flask, a solution of 3.2 g (9.35 mmol) of methyl2-[(4-cyclohexylphenoxy)methyl]-5-fluorobenzoate from Ex. XI in 20 ml ofether is added dropwise such that the reaction mixture is just boiling.After 30 minutes, the reaction mixture is diluted with ether, and 20%strength aqueous potassium sodium tartrate solution is added carefully.The organic phase is separated off and washed successively with waterand saturated sodium chloride solution. Drying over Na₂SO₄. Afterfiltration and concentration using a rotary evaporator, 2.57 g (8.17mmol, 87% yield) of product are obtained as a white solid.

R_(f) (cyclohexane/ethyl acetate 9:1): 0.13. ¹H-NMR (300 MHz, DMSO-d₆,δ/ppm): 7.45 (1H, dd), 7.27 (1H, dd), 7.12 (2H, d), 7.06 (1H, dt), 6.91(2H, d), 5.31 (1H, t), 5.03 (2H, s), 4.60 (2H, d), 2.48-2.38 (1H, m),1.80-1.66 (5H, m), 1.42-1.18 (5H, m). MS (DCI, NH₃): 646 (2M+NH₄ ⁺), 332(M+NH₄ ⁺).

Ex. XIII 2-(Bromomethyl)-1-[(4-cyclohexylphenoxy)methyl]-4-fluorobenzene

A solution of 2.5 g (7.95 mmol) of{2-[(4-cyclohexylphenoxy)methyl]-5-fluorophenyl-}methanol from Ex. XIIin 30 ml of ether is added to a solution of 2.5 g (9.54 mmol) oftriphenylphosphine and 3.2 g (9.54 mmol) of carbon tetrabromide in 30 mlof ether. After 20 hours of stirring at room temperature, a further 0.83g of triphenylphosphine and 1.05 g of carbon tetrabromide solid areadded. After six hours, the mixture is evaporated to dryness and theproduct is isolated by flash chromatography (silica gel,cyclohexane/ethyl acetate 50:1). This gives 2.3 g (6.1 mmol, 77% yield)of a colorless solid having low melting point.

R_(f) (cyclohexane/ethyl acetate 9:1): 0.50. ¹H-NMR (300 MHz, DMSO-d₆,δ/ppm): 7.52 (1H, dd), 7.39 (1H, dd), 7.20 (1H, dt), 7.15 (2H, d), 6.95(2H, d), 5.17 (2H, s), 4.79 (2H, s), 2.50-2.39 (1H, m), 1.80-1.65 (5H,m), 1.42-1.18 (5H, m). MS (EI+): 376/378 (M⁺).

Ex. XIV {2-[(4-Cyclohexylphenoxy)methyl]-5-fluorophenyl}acetonitrile

6 ml (5.96 mmol) of a 1-molar solution of tetra-n-butylammonium fluoridein THF is added to a solution of 0.8 ml (5.96 mmol) of trimethylsilylcyanide in 5 ml of acetonitrile. After five minutes, a solution of 1.5 g(3.98 mmol) of2-(bromomethyl)-1-[(4-cyclohexylphenoxy)methyl]-4-fluorobenzene from Ex.XIII in 5 ml of acetonitrile is added. The reaction mixture is stirredat room temperature for 30 minutes. The mixture is then evaporatedcompletely using a rotary evaporator and the product is isolated byflash chromatography (silica gel, cyclohexane/ethyl acetate 20:1). Thisgives 1.15 g (3.56 mmol, 89% yield) of a white solid.

R_(f) (cyclohexane/ethyl acetate 4:1): 0.53. ¹H-NMR (300 MHz, DMSO-d₆,δ/ppm): 7.57 (1H, dd), 7.31 (1H, dd), 7.22 (1H, dt), 7.14 (2H, d), 6.95(2H, d), 5.10 (2H, s), 4.11 (2H, s), 2.48-2.39 (1H, m), 1.80-1.66 (5H,m), 1.42-1.18 (5H, m). MS (DCI, NH₃): 664 (2M+NH₄ ⁺), 358 (M+NH₃+NH₄ ⁺),341 (M+NH₄ ⁺).

Ex. XV 2-{2-[(4-Cyclohexylphenoxy)methyl]-5-fluorophenyl}ethylaniine

810 mg (2.50 mmol) of{2-[(4-cyclohexylphenoxy)methyl]-5-fluorophenyl}-acetonitrile from Ex.XIV are initially charged in 20 ml of anhydrous THF, and 2.53 ml (5.01mmol) of a 2-molar solution of borane/dimethyl sulfide complex in THFare added. The mixture is heated at reflux for 2 hours. The mixture isthen cooled, acidified using dilute hydrochloric acid and again brieflyheated to reflux. The mixture is then once more allowed to cool and madealkaline using dilute aqueous sodium hydroxide solution. The mixture isextracted with ether. The organic phase is washed successively withwater and saturated sodium chloride solution. Drying over Na₂SO₄.Filtration and concentration gives 820 mg (2.5 mmol, 100% yield) of apale yellow oil which is used for the next step without furtherpurification.

R_(f) (ethyl acetate/methanol 7:3): 0.12. ¹H-NMR (300 MHz, DMSO-d₆,δ/ppm): 7.45 (1H, dt), 7.15-7.00 (4H, m), 6.92 (2H, d), 5.02 (2H, s),2.78-2.70 (4H, m), 2.50-2.40 (1H, m), 1.92 (2H, broad), 1.80-1.65 (5H,m), 1.42-1.20 (5H, m). MS (DCI, NH₃): 328 (M+H⁺).

Ex. XVI Methyl4-{[(2-{2-[(4-cyclohexylphenoxy)methyl]-5-fluorophenyl}ethyl)amino]methyl}benzoate

700 mg (2.14 mmol) of2-{2-[(4-cyclohexylphenoxy)methyl]-5-fluorophenyl}ethylamine from Ex. XVand 316 mg (1.92 mmol) of methyl 4-formylbenzoate in 50 ml of tolueneare boiled in a water separator for 30 minutes. The mixture is thenconcentrated by evaporation and the residue is taken up in 20 ml ofmethanol. With ice-cooling, 81 mg (2.14 mmol) of solid NaBH₄ are added alittle at a time. The mixture is stirred at room temperature for 30minutes. The mixture is then neutralized with 5% strength aqueousNaH₂PO₄ solution, diluted with water and extracted with ether. Theorganic phase is washed successively with water and saturated sodiumchloride solution. Drying over Na₂SO₄. The product is isolated by flashchromatography (silica gel, cyclohexane/ethyl acetate 3:1). This gives730 mg (1.53 mmol, 80% yield) of a colorless oil.

R_(f) (cyclohexane/ethyl acetate 1:2): 0.40. ¹H-NMR (300 MHz, DMSO-d₆,δ/ppm): 7.87 (2H, d), 7.45-7.39 (3H, m), 7.12-7.08 (3H, m), 7.02 (1H,dt), 6.85 (2H, d), 5.00 (2H, s), 3.83 (3H, s), 3.76 (2H, s), 2.83-2.70(4H, m), 2.47-2.39 (1H, m), 1.74 (1H, s broad), 1.80-1.64 (5H, m),1.39-1.18 (5H, m). MS (ESI): 476 (M+H⁺).

Ex. XVII Methyl4-{[(2-{2-[(4-cyclohexylphenoxy)methyl]-5-fluorophenyl}ethyl)(5-methoxy-5-oxopentyl)amino]methyl}benzoate

720 mg (1.51 mmol) of4-{[(2-{2-[(4-cyclohexylphenoxy)methyl]-5-fluorophenyl}ethyl)amino]methyl}benzoatefrom Ex. XVI, 242 μl (1.82 mmol) of methyl 5-bromovalerate and 193 mg(1.82 mmol) of anhydrous sodium carbonate and 20 ml of butyronitrile areheated at reflux. After 48 hours, the mixture is concentrated byevaporation, taken up in ethyl acetate and washed successively withwater and saturated sodium chloride solution. Drying over Na₂SO₄. Theproduct is purified by flash chromatography (silica gel,cyclohexane/ethyl acetate 9:1). This gives 570 mg (0.97 mmol, 64% yield)of a colorless oil.

R_(f) (cyclohexane/ethyl acetate 2:1): 0.56. ¹H-NMR (300 MHz, DMSO-d₆,δ/ppm): 7.83 (2H, d), 7.42 (1H, dd), 7.37 (2H, d), 7.10 (2H, d),7.08-6.99 (2H, m), 6.83 (2H, d), 4.93 (2H, s), 3.83 (3H, s), 3.62 (2H,s), 3.55 (3H, s), 2.80 (2H, dd), 2.63 (2H, dd), 2.48-2.37 (3H, m), 2.15(2H, t), 1.80-1.65 (5H, m), 1.42-1.14 (9H, m). MS (ESI): 590 (M+H⁺).

Synthesis Examples Ex. 14-({(4-Carboxybutyl)[3-(4-cyclohexylphenoxy)benzyl]amino}methyl)benzoicacid

195 μl of a 45% strength solution of NaOH in water are added to asolution of 352 mg (0.65 mmol) of methyl4-{[[3-(4-cyclohexylphenoxy)benzyl](5-methoxy-5-oxopentyl)amino]methyl}benzoatefrom Ex. IV in 3.5 ml of dioxane and 1.8 ml of water, and the mixture isstirred at 90° C. for 2 hours. After cooling, the dioxane is removedunder reduced pressure and the aqueous phase is adjusted to pH 4-5 using1-molar hydrochloric acid. This results in the precipitation of theproduct, which is filtered off, washed with water and dried. This gives280 mg (0.54 mmol, 83% yield) of a white solid.

R_(f) (ethyl acetate/methanol 7:3): 0.38. ¹H-NMR (300 MHz, DMSO-d₆,δ/ppm): 12.49 (2H, broad s), 7.89 (2H, d), 7.47 (2H, d), 7.29 (1H, t),7.20 (2H, d), 7.05 (1H, d), 6.98-6.80 (4H, m), 3.55 (2H, s), 3.50 (2H,s), 2.51 (1H, m partially obscured by DMSO), 2.41 (2H, m), 2.08 (2H, m),1.89-1.62 (6H, m), 1.49-1.13 (8H, m). MS (ESI): 1030 (2M+H+), 516(M+H⁺).

The following compound was obtained in an analogous manner:

Ex. Formula ¹H-NMR δ[ppm](DMSO-d₆) 2 (from 4-(4-tri- fluoromethyl-phenyl)-phenol

12.36(2H, broad), 7.79-7.69 (8H, m), 7.45-7.40(3H, m), 7.21-7.01(4H, m),6.95(1H, d), 3.59(2H, s), 3.51(2H, s), 2.41-2.29(2H, m), 2.17-2.02 (2H,m), 1.55-1.34(4H, m). (300 MHz)

Ex. 34-({(4-Carboxybutyl)[3-(4-cyclohexylphenoxy)benzyl]amino}methyl)-benzoicacid hydrochloride

0.5 ml (2 mmol) of a 4-molar solution of HCl in dioxane is added to asolution of 220 mg (0.43 mmol) of4-({(4-carboxybutyl)[3-(4-cyclohexylphenoxy)benzyl]-amino}methyl)benzoicacid from Ex. 1 in 0.2 ml of dioxane, and the mixture is stirred at 60°C. for 1 h. The mixture is then concentrated by evaporation and theresulting colorless oil is repeatedly triturated with diethyl ether. Theresulting crystals are filtered and dried. This gives 171 mg (0.31 mmol,72% yield) of a white solid.

R_(f) (ethyl acetate/methanol 7:3): 0.42. ¹H-NMR (300 MHz, DMSO-d₆,δ/ppm): 12.50 (2H, broad s), 10.47 (1H, broad s), 7.99 (2H, d), 7.66(2H, d), 7.49 (1H, t), 7.35 (1H, d), 7.25 (3H, d), 7.06 (1H, d), 6.95(2H, m), 3.40 (2H, d) 3.45 (2H, d), 2.92 (2H, m), 2.51 (1H, m partiallyobscured by DMSO), 2.20 (2H, t), 1.89-1.62 (7H, m), 1.49-1.15 (7H, m).MS (ESI): 516 (M+H⁺−HCl).

The following compounds are obtained in an analogous manner:

¹H-NMR δ[ppm] Ex. Formula (DMSO-d₆) 4 (from 2)

12.5(2H, broad), 10.45 (1H, broad), 7.96(2H, d), 7.88(2H, d), 7.84-7.72(3H, m), 7.65(2H, d), 7.55-7.18(4H, m), 7.15 (2H, d), 6.93(1H, d),4.43-4.28(4H, m), 3.02-2.88 (2H, m), 2.19(2H, t), 1.88-1.66(2H, m),1.50-1.32(2H, m). (300 MHz) 5 from 4-(4-fluoro- phenyl)- phenol

12.74(2H, broad), 10.79 (1H, broad), 7.97(2H, d), 7.78-7.57(6H, m),7.53-7.02 (8H, m), 4.49-4.21 (4H, m), 3.02-2.80(2H, m), 2.20(2H, t),1.88 (2H, m), 1.51-1.28(2H, m). (200 MHz)

Ex. 64-({(4-Carboxybutyl)[2-(2-{difluoro[4′-(trifluoromethyl)-1,1′-biphenyl-4-yl]methoxy}phenyl)ethyl]amino}methyl)benzoicacid

125 mg (0.19 mmol) of methyl4-{[[(2-(2-difluoro[4′-(trifluoromethyl)-1,1′-biphenyl4-yl]methoxy}phenyl)ethyl](5-methoxy-5-oxopentyl)amino]methyl}-benzoatefrom Ex. X are heated at 60° C. in a mixture of 2 ml of THF, 1 ml ofmethanol and 3 ml of 2-molar aqueous LiOH solution for 1.5 hours. Mostof the organic solvents are then removed using a rotary evaporator. Theresulting aqueous solution is initially washed with ether and thenadjusted to pH 4-5 using 1-molar hydrochloric acid. The mixture isextracted with ethyl acetate. The organic phase is dried over Na₂SO₄.Filtration and evaporation gives 107 mg of crude product which arepurified by HPLC. The product fractions are combined and recrystallizedfrom methanol. This gives 83 mg (0.13 mmol) of a white solid.

R_(f) (ethyl acetate/methanol 7:3): 0.48. ¹H-NMR (200 MHz, DMSO-d₆,δ/ppm): 12.38 (2H, broad), 7.98-7.77 (10H, m), 7.37-7.18 (6H, m), 3.59(2H, s), 2.81 (2H, dd), 2.61 (2H, dd), 2.41 (2H, t), 2.08 (2H, t),1.44-1.32 (4H, m). MS (ESI): 642 (M+H⁺).

The following compounds were prepared in an analogous manner:

¹H-NMR δ[ppm] Ex. Formula (DMSO-d₆) 7 (analogously to 6, but usingbenzene- boronic acid)

12.08(2H), 7.83-7.77 (6H, m), 7.71(2H, d), 7.52-7.41(3H, m), 7.37-7.18(6H, m), 3.61(2H, s), 2.82(2H, m), 2.61 (2H, m), 2.42(2H, m), 2.08(2H,m), 1.40(4H, m). (300 MHz) 8 (analogously to 6, but using 4-t-butyl-benzene- boronic acid)

12.22(2H, broad), 7.82-7.74 (6H, m), 7.63(2H, d), 7.51(2H, d), 7.33-7.28(5H, m), 7.26-7.18 (1H, m), 3.60(2H, s), 2.81(2H, dd), 2.61(2H, dd),2.41(2H, t), 2.09 (2H, t), 1.42-1.37(4H, m), 1.33(9H, s). (300 MHz) 9(analogously to 6, but using 4-chloro- benzene- boronic acid)

12.42(2H, broad), 7.87-7.72 (8H, m), 7.56(2H, d), 7.33-7.18(6H, m),3.60(2H, s), 2.81(2H, dd), 2.60(2H, dd), 2.43-2.37 (2H, m), 2.12-2.04(2H, m), 1.42-1.34(4H, m). (200 MHz) 10 (analogously to 6, but using4-methoxy- benzene- boronic acid)

12.40(2H, broad), 7.87-7.63 (8H, m), 7.39-7.20 (6H, m), 7.07(2H, d),3.82(2H, s), 3.61(2H, broad), 2.82(2H, broad), 2.62(2H, broad), 2.41(2H, broad), 2.10(2H, broad), 1.39(4H, broad). (200 MHz)

Ex. 114-({(4-Carboxybutyl)[2-(2-{difluoro[-1,1′-biphenyl-4-yl]methoxy}phenyl)ethyl]amino}methyl)benzoicacid hydrochloride

This compound was prepared from Ex. 7 analogously to Ex. 3.

¹H-NMR: δ [ppm] DMSO-d₆: 12.70 (2H, broad), 10.49 (1H, broad), 7.97 (2H,d), 7.83 (4H, s), 7.73-7.68 (4H, m), 7.57-7.29 (7H, m), 4.47 (2H, sbroad), 3.20-3.15 (6H, m), 2.18 (2H, t), 1.79-1.63 (2H, m), 1.52-1.49(2H, m). (200 MHz)

Ex. 124-{[(4-Carboxybutyl)(2-{2-[(4-cyclohexylphenoxy)methyl]-5-fluorophenyl}ethyl)amino]methyl}benzoicacid

500 mg (0.85 mmol) of methyl4-{[(2-{2-[(4-cyclohexylphenoxy)methyl]-5-fluorophenyl}ethyl)(5-methoxy-5-oxopentyl) amino]methyl} benzoate from Ex. XVII aredissolved in 5 ml of THF, and 20 ml of 2-molar aqueous sodium hydroxidesolution are added. The mixture is heated at 50-60° C. for 15 hours.After cooling, the mixture is extracted with ether and the aqueous phaseis then adjusted to pH 4-5 using 2-molar hydrochloric acid. The productprecipitates in the form of a white solid which is filtered off withsuction and washed with water. This gives 420 mg (0.75 mmol, 88% yield).

Melting point: >250° C.

R_(f) (ethyl acetate/methanol 7:3): 0.43. ¹H-NMR (300 MHz, DMSO-d₆,δ/ppm): 12.52 (2H, broad), 7.81 (2H, d), 7.42 (1H, dd), 7.27 (2H, d),7.11 (2H, d), 7.08-6.98 (2H, m), 6.84 (2H, d), 4.93 (2H, s), 3.59 (2H,s), 2.79 (2H, dd), 2.63 (2H, dd), 2.48-2.37 (3H, m), 2.11-2.04 (2H, m),1.79-1.63 (5H, m), 1.41-1.16 (9H, m). MS (ESI): 562 (M+H⁺).

The following compounds were obtained in an analogous manner:

Ex. Formula Analytical data 13 (analogously to 12, but using 4-t-butyl-phenol)

Melting point(° C.): >250 MS(ESI): 536(M + H⁺) 14 (analogously to 12,but using 4-(4-fluoro- phenyl)phenol)

¹H-NMR(300MHz): δ [ppm]: (DMSO-d₆): 12.19 (2H, broad), 7.83(2H, d),7.67-7.61(2H, m), 7.57 (2H, d), 7.47(1H, dd), 7.35 (2H, d), 7.27(2H,dd), 7.10-7.02(4H, m), 5.03 (2H, s), 3.63(2H, s), 2.82 (2H, dd),2.66(2H, #dd), 2.43(2H, 2.11(2H, 1.40 (4H) 15 (analogously to 12, butusing 4-(4-methoxy- phenyl- phenol)

¹H-NMR(300MHz): δ [ppm]: (DMSO-d₆): 12.49 (2H, broad), 7.83(2H, d),7.53(2H, d), 7.52(2H, d), 7.47(1H, dd), 7.33(2H, d), 7.09-6.97(6H, m),5.02 (2H, s), 3.78(3H, s), 3.63 (2H, s), 2.82(2H, dd), 2.66 (2H, #dd),2.43(2H, pseudo-t), 2.11(2H, pseudo-t), 1.41 (4H). 16 (analogously to12, but using 4-(4-chloro- phenyl)- phenol)

12.38(2H, broad), 7.83 (2H, d), 7.64(2H, d), 7.60 (2H, d), 7.50-7.47(3H,m), 7.36(2H, d), 7.10-7.02(4H, m), 5.05(2H, s), 3.63(2H), 2.82(2H),2.66(2H), 2.43 (2H), 2.10(2H), 1.41(4H). (300 MHz) 17 (analogously to12, but using 4-(4-tri- fluorometh- ylphenyl)- phenol)

12.40(2H, broad), 7.87-7.74 (6H, m), 7.68(2H, d), 7.48(1H, dd), 7.33(2H,d), 7.10-7.00(4H, m), 5.07 (2H, s), 3.63(2H, s), 2.82 (2H, dd), 2.68(2H,dd), 2.43(2H), 2.11(2H), 1.41 (4H). (200 MHz) 18 (analogously to 12, butusing 4-(4-cyano- phenyl) phenol)

12.32(2H, broad), 7.91-7.80 (6H, m), 7.71(2H, d), 7.48(1H, dd), 7.34(2H,d), 7.09-7.00(4H, m), 5.07 (2H, s), 3.64(2H, s), 2.82 (2H), 2.67(2H),2.43(2H), 2.10(2H), 1.40(4H). (200 MHz) 19 (analogously to 12, but using4-(4-trifluoro- methylphenyl) phenol and methyl 2-bromo- methyl-benzoate)

12.39(2H, broad), 7.87-7.74 (6H, m), 7.68(2H, d), 7.44-7.33(3H, m),7.29-7.17 (3H, m), 7.07(2H, d), 5.07(2H, s), 3.66(2H, s), 2.82(2H, dd),2.66(2H, dd), 2.45 #(2H, partially obscured by DMSO), 2.11 (2H),1.42(4H). (200 MHz) 20 (analogously to 12, but using 4-(4-methoxy-phenyl)phenol and methyl 2-bromo- methyl- benzoate)

12.37(2H, broad), 7.83 (2H, d), 7.53(2H, d), 7.52 (2H, d), 7.42-7.37(3H,m), 7.30-7.19(3H, m), 6.98 (4H, d), 5.04(2H, s), 3.78 3H, s), 3.65(2H,s), 2.81 (2H, dd), 2.64(2H, #dd), 2.45(2H, partially obscured by DMSO),2.11(2H), 1.42 (4H). (300 MHz) 21 (analogously to 12, but using4-(4-chloro- phenyl) phenol and methyl 2-bromo- methyl- benzoate)

12.39(2H, broad), 7.82 (2H, d), 7.63(2H, d), 7.59 (2H, d), 7.49-7.34(5H,m), 7.28-7.17(3H, m), 7.02 (2H, d), 5.07(2H, s), 3.65 (2H, s), 2.80(2H,dd), 2.63 (2H, dd), 2.45 #(2H, partially obscured by DMSO), 2.11 (2H),1.42(4H). (200 MHz)

1. A compound of the general formula (I)

in which R¹ is located in the meta- or para-position to the radical Wand represents a radical selected from the group consisting of H,halogen and OCF₃; R² represents H, or halogen; R³ represents H orhalogen; R⁴ represents C₁₋₆-alkyl, C₃₋₈-cycloalkyl, CF₃, OCF₃, F, Cl,OMe or phenyl, where the phenyl radical may additionally carry asubstituent selected from the group consisting of halogen, CN,C₁₋₆-alkoxy, CF₃, C₁₋₆-alkyl; V is located in the ortho- ormeta-position to the radical W and represents O, CH₂O, OCF₂ orO—C₁₋₆-alkyl-O; W represents CH₂ or CH₂CH₂; or a pharmaceuticallyacceptable salt or stereoisomer thereof.
 2. The compound as claimed inclaim 1, wherein R¹ is located in the meta-position to the radical W andrepresents H or halogen; R² represents H or halogen; R³ represents H orhalogen; R⁴ represents C₁₋₆-alkyl, C₃₋₈-cycloalkyl or phenyl, where thephenyl radical may additionally carry a substituent selected from thegroup consisting of halogen, CN, C₁₋₆-alkoxy, CF₃, C₁₋₆-alkyl; V islocated in the ortho- or meta-position to the radical W and representsO, CH₂O, OCF₃ or O—C₁₋₆-alkyl-O; W represents CH₂ or CH₂CH₂; or apharmaceutically acceptable salt or stereoisomer thereof.
 3. Thecompound as claimed in claim 1, wherein R¹ is located in themeta-position to the radical W and represents a radical selected fromthe group consisting of H, F, Cl and Br; R² represents H, R³ representsH; R⁴ represents methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl,where the phenyl radical may additionally carry a substituent from thegroup consisting of F, Cl, Br, CN, methoxy, ethoxy, n-propoxy,i-propoxy, n-butyloxy, i-butyloxy, t-butyloxy, CF₃, methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, t-butyl; V is located in theortho- or meta-position to the radical W and represents O, CH₂O, OCF₂ orO—C₁₋₆-alkyl-O; W represents CH₂ or CH₂CH₂; or a pharmaceuticallyacceptable salt or stereoisomer thereof.
 4. The compound as claimed inclaim 1, wherein R¹ is located in the meta-position to the radical W andrepresents H; R² represents H; R³ represents H; R⁴ representscyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl, where thephenyl radical may additionally carry a substituent from the groupconsisting of F, Cl, Br, CF₃; V is located in the meta-position to theradical W and represents O; W represents CH₂; or a pharmaceuticallyacceptable salt or stereoisomer thereof.
 5. The compound as claimed inclaim 1, characterized in that wherein R¹ is located in themeta-position to the radical W and represents H; R² represents H; R³represents H; R⁴ represents phenyl, where the phenyl radical mayadditionally carry a substituent from the group consisting of F, Cl, Br,OMe, CF₃, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl;V is located in the ortho-position to the radical W and represents OCF₂;W represents CH₂CH₂; or a pharmaceutically acceptable salt orstereoisomer thereof.
 6. The compound as claimed in claim 1, wherein R¹is located in the meta-position to the radical W and represents aradical selected from the group consisting of H, F, Cl and Br; R²represents H; R³ represents H; R⁴ represents methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, or phenyl, where the phenyl radical mayadditionally carry a substituent selected from the group consisting ofF, Cl, Br, CN, OMe, CF₃, methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, t-butyl; V is located in the ortho-position to the radical Wand represents CH₂O; W represents CH₂CH₂; or a pharmaceuticallyacceptable salt or stereoisomer thereof.
 7. A process for preparingcompounds of the general formula (I), comprising the following steps:compounds of the formula (II)

 in which R¹, V and W are as defined in claim 1 and L, if V is O,represents methyl or otherwise represents a radical of the formula

 where R², R³ and R⁴ are as defined in claim 1, with a C₁₋₆-alkyl4-formylbenzoate in an organic solvent, to give a compound of theformula (III)

in which R¹, V, W and L are as defined above and Q represents aC₁₋₆-alkyl radical, then reacting with a C₁₋₆-alkyl ω-halovalerate in anorganic solvent in the presence of a base with heating to give compoundsof the formula (IV)

in which R¹, V, W, and Q are as defined above, Q′ represents aC₁₋₆-alkyl radical and L represents H— if V is O— or a radical of theformula II-A, then—if V is O and L represents H—reacting the compound ofthe formula (IV) with a compound of the formula IV-A in an organicsolvent with heating

where R² and R³ are as defined in claim 1 and X and X′ each representhalogen, followed by palladium-catalyzed substitution of the radical Xwith a benzene boronic acid derivative to give compounds of the formula(V)

and subsequent hydrolysis of the compounds of the formula (IV) or (V)under alkaline conditions to give the compounds of the formula (I). 8.The process of claim 7 wherein the step of reacting the compound offormula (II) with a C₁₋₆-alkyl 4-formylbenzoate is carried out withheating and simultaneous or subsequent addition of a reducing agent. 9.The process of claim 7 wherein in the step of reacting the compound offormula (III) with a C₁₋₆-alkyl ω-haolvalerate, the compound of formula(III) is first subjected to prior cleavage of the ether to give the freehydroxyl group, if V represents O and L represents methyl.
 10. Apharmaceutical composition comprising a compound according to claim 1and a pharmaceutically acceptable carrier.
 11. A method for treating acardiovascular disorder selected from angina pectoris, ischemias,hypertension, and arteriosclerosis comprising administering to a subjectin need thereof an effective amount of a compound of claim
 1. 12. Amethod for treating fibrosis of the liver comprising administering to asubject in need thereof an effective amount of a compound of claim 1.